ABSTRACT The Immunity-Related GTPases (IRG) are a family of genes that are induced by interferon gamma and/or LPS and play pivotal roles in immune responses. Human IRGM gene variants are associated with increased risk of Crohn?s Disease (CD) and other inflammatory diseases. Mice lacking an IRGM orthologue, Irgm1, exhibit a similar spectrum of inflammatory and immune disorders, including increased intestinal inflammation. Despite the profound consequences of deficiencies in IRGM proteins, the basic mechanisms through which they function remain unclear. Based on preliminary data, we hypothesize that deficiencies in IRGM proteins lead to metabolic dysregulation of T cells, influencing both effector and regulatory T cell subsets, resulting in immune dysfunction and inflammatory disease. The following aims will test this hypothesis: Aim 1. Define functional deficiencies among T cell subsets lacking Irgm1 and determine the underlying mechanism including the role of altered cellular metabolism. Comprehensive functional analyses of T cells from Irgm1-/- mice will be used to determine differences in T cell development and functional output. The mechanism underlying any alterations will be determined by first defining a metabolic signature among Irgm1-deficient T cell subsets, and then applying genetic or pharmacologic interventions to mitigate metabolic changes and determine whether this normalizes T cell dysfunction. In addition, we will use a conditional T-cell specific Irgm1-deficient mouse to determine if the impact on T cell function/metabolism is cell-intrinsic. Lastly, the role of Irgm1-regulated autophagy in metabolic alterations will be addressed through pharmacological approaches. Aim 2. Identify the role of Irgm1 in a mouse model of T cell-mediated intestinal inflammation. To determine whether altered Teff and/or Treg cell function, as a result of Irgm1-deficiency, alter the development of intestinal inflammation, a T cell transfer model of colitis will be tested using T cells from WT and Irgm1-/- mice. Additionally, T cells lacking both Glut1 and Irgm1 will be used to test the role of increased glucose metabolism in Irgm1-dependent T cell dysfunction in the intestinal inflammation model. Aim 3. Determine the impact of IRGM gene variants on T cell metabolism and function in a human cohort. Human T cells from a large cohort of individuals genotyped for IRGM CD risk variants will be used in T cell metabolic analyses and assessments of in vitro immune and inflammatory function. Potential correlations between altered T cell metabolism and immune cell dysfunction will be investigated, as will the impact of normalization of T cell metabolism on function. Collectively, these studies will validate a new mechanistic paradigm through which deficiency in IRGM proteins leads to immune dysfunction and inflammation. This work will be innovative by producing a conceptual shift in our understanding of how IRGM proteins function. This can be translated into identifying metabolic pathways that can be targeted for molecular diagnostics and novel therapies for CD and other inflammatory syndromes.